Epigenetic Reprogramming of Autophagy Drives Mutant IDH1 Glioma Progression and Response to Radiation.

Mutant isocitrate dehydrogenase 1 (mIDH1; IDH1 R132H ) exhibits a gain of function mutation enabling 2-hydroxyglutarate (2HG) production. 2HG inhibits DNA and histone demethylases, inducing epigenetic reprogramming and corresponding changes to the transcriptome. We previously demonstrated 2HG-mediated epigenetic reprogramming enhances DNA-damage response and confers radioresistance in mIDH1 gliomas harboring p53 and ATRX loss of function mutations. In this study, RNA-seq and ChIP-seq data revealed human and mouse mIDH1 glioma neurospheres have downregulated gene ontologies related to mitochondrial metabolism and upregulated autophagy. Further analysis revealed that the decreased mitochondrial metabolism was paralleled by a decrease in glycolysis, rendering autophagy as a source of energy in mIDH1 glioma cells. Analysis of autophagy pathways showed that mIDH1 glioma cells exhibited increased expression of pULK1-S555 and enhanced LC3 I/II conversion, indicating augmented autophagy activity. This dependence is reflected by increased sensitivity of mIDH1 glioma cells to autophagy inhibition. Blocking autophagy selectively impairs the growth of cultured mIDH1 glioma cells but not wild-type IDH1 (wtIDH1) glioma cells. Targeting autophagy by systemic administration of synthetic protein nanoparticles packaged with siRNA targeting Atg7 (SPNP-siRNA-Atg7) sensitized mIDH1 glioma cells to radiation-induced cell death, resulting in tumor regression, long-term survival, and immunological memory, when used in combination with IR. Our results indicate autophagy as a critical pathway for survival and maintenance of mIDH1 glioma cells, a strategy that has significant potential for future clinical translation. One Sentence Summary: The inhibition of autophagy sensitizes mIDH1 glioma cells to radiation, thus creating a promising therapeutic strategy for mIDH1 glioma patients. Graphical abstract: Our genetically engineered mIDH1 mouse glioma model harbors IDH1 R132H in the context of ATRX and TP53 knockdown. The production of 2-HG elicited an epigenetic reprogramming associated with a disruption in mitochondrial activity and an enhancement of autophagy in mIDH1 glioma cells. Autophagy is a mechanism involved in cell homeostasis related with cell survival under energetic stress and DNA damage protection. Autophagy has been associated with radio resistance. The inhibition of autophagy thus radio sensitizes mIDH1 glioma cells and enhances survival of mIDH1 glioma-bearing mice, representing a novel therapeutic target for this glioma subtype with potential applicability in combined clinical strategies.

Diagnostic Approach to Interstitial Lung Diseases Associated with Connective Tissue Diseases.

Interstitial lung disorders are a group of respiratory diseases characterized by interstitial compartment infiltration, varying degrees of infiltration, and fibrosis, with or without small airway involvement. Although some are idiopathic (e.g., idiopathic pulmonary fibrosis, idiopathic interstitial pneumonias, and sarcoidosis), the great majority have an underlying etiology, such as systemic autoimmune rheumatic disease (SARD, also called Connective Tissue Diseases or CTD), inhalational exposure to organic matter, medications, and rarely, genetic disorders. This review focuses on diagnostic approaches in interstitial lung diseases associated with SARDs. To make an accurate diagnosis, a multidisciplinary, personalized approach is required, with input from various specialties, including pulmonary, rheumatology, radiology, and pathology, to reach a consensus. In a minority of patients, a definitive diagnosis cannot be established. Their clinical presentations and prognosis can be variable even within subsets of SARDs.

Nonequilibrium Anion Detection in Solid-Contact Ion-Selective Electrodes.

Low-cost and portable nitrate and phosphate sensors are needed to improve farming efficiency and reduce environmental and economic impact arising from the release of these nutrients into waterways. Ion selective electrodes (ISEs) could provide a convenient platform for detecting nitrate and phosphate, but existing ionophore-based nitrate and phosphate selective membrane layers used in ISEs are high cost, and ISEs using these membrane layers suffer from long equilibration time, reference potential drift, and poor selectivity. In this work, we demonstrate that constant current operation overcomes these shortcomings for ionophore-based anion-selective ISEs through a qualitatively different response mechanism arising from differences in ion mobility rather than differences in ion binding thermodynamics. We develop a theoretical treatment of phase boundary potential and ion diffusion that allows for quantitative prediction of electrode response under applied current. We also demonstrate that under pulsed current operation, we can create functional solid-contact ISEs using lower-cost molecularly imprinted polymers (MIPs). MIP-based nitrate sensors provide comparable selectivity against chloride to costlier ionophore-based sensors and exhibit >100,000 times higher selectivity against perchlorate. Likewise, MIP-based solid contact ion-selective electrode phosphate sensors operated under pulsed current provide competitive selectivity against chloride, nitrate, perchlorate, and carbonate anions. The theoretical treatment and conceptual demonstration of pulsed-current ISE operation we report will inform the development of new materials for membrane layers in ISEs based on differences in ion mobility and will allow for improved ISE sensor designs.

Laparoscopic Cholecystectomy vs Endoscopic Retrograde Cholangiopancreatography With Sphincterotomy in Elderly Patients With Acute Gallstone Pancreatitis.

BACKGROUND: Gallstone pancreatitis (GSP) is common in elderly patients and carries worse outcomes. Laparoscopic cholecystectomy (LC) is recommended for prevention of recurrent GSP. In frail populations, an endoscopic retrograde cholangiopancreatography with sphincterotomy (ERCP-s) is an alternative. Management guidelines of GSP in the elderly are lacking. This study aimed to investigate and compare management strategies for GSP in the elderly. MATERIALS AND METHODS: A retrospective comparison of outcome of patients aged ≥65 years with first presentation of GSP treated either with (1) LC only, (2) ERCP-s, (3) ERCP-S followed by LC, or (4) no intervention. RESULTS: 216 patients were included. Median age was 76 years (interquartile range 70-83). Most (80%, n = 172) had mild pancreatitis, whilst 12% (n = 26) had severe disease. 24% (n = 55) were treated with ERCP-s; 40% (n = 87) underwent LC alone; 11% (n = 23) had ERCP-s followed by LC; and 25% (n = 55) received no intervention. Patients without intervention were older (P < .001) and frailer (P < .001). The LC-only group had lower post-procedure re-admission rates of 6% (n = 5) compared to 27% (n = 14) for ERCP-s, 33% (n = 7) for ERCP-S + LC, and 31% (n = 17) for the no intervention group (P = .0001). Biliary cause mortality was highest in the no intervention group (n = 11, 20%). CONCLUSION: Laparoscopic cholecystectomy represents the gold standard for elderly patients with GSP.

Proteinase 3-specific antineutrophil cytoplasmic antibody-associated vasculitis.

Proteinase 3 (PR3)-specific antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is one of two major ANCA-associated vasculitis variants and is pathogenically linked to granulomatosis with polyangiitis (GPA). GPA is characterised by necrotising granulomatous inflammation that preferentially affects the respiratory tract. The small vessel vasculitis features of GPA are shared with microscopic polyangiitis. Necrotising granulomatous inflammation of GPA can lead to PR3-ANCA and small vessel vasculitis via activation of neutrophils and monocytes. B cells are central to the pathogenesis of PR3-ANCA-associated vasculitis. They are targeted successfully by remission induction and maintenance therapy with rituximab. Relapses of PR3-ANCA-associated vasculitis and toxicities associated with current standard therapy contribute substantially to remaining mortality and damage-associated morbidity. More effective and less toxic treatments are sought to address this unmet need. Advances with cellular and novel antigen-specific immunotherapies hold promise for application in autoimmune disease, including PR3-ANCA-associated vasculitis. This Series paper describes the inter-related histopathological and clinical features, pathophysiology, as well as current and future targeted treatments for PR3-ANCA-associated vasculitis.

Clostridium difficile Infection Prior to Total Hip Arthroplasty Independently Increases the Risk of Periprosthetic Joint Infection.

BACKGROUND: Periprosthetic joint infection (PJI) following total hip arthroplasty (THA) is associated with major morbidity. There may be a link between the gut microbiome and an individual's overall immune system. A Clostridium difficile (C. difficile) infection portends poor gut microbiome health and has been previously associated with increased 90-day complication rates in total joint arthroplasty (TJA). The purpose of this study was to determine the effect of a previous history of C. difficile infection within 2 years of undergoing THA on PJI within 2 years postoperatively. METHODS: Patients undergoing THA from 2010 to 2021 were identified in a patient claims database (n = 770,075). Patients who had active records 2 years before and after THA as well as a history of C. difficile infection within 2 years prior to THA (n = 1,836) were included and propensity matched to a control group using age, sex, and Elixhauser comorbidity index. The primary outcome was the 2-year incidence of postoperative PJI. The exposed C. difficile infection cohort was stratified into 4 groups based on the time proximity of the C. difficile infection. Chi-square tests and logistic regressions were used to compare the groups. RESULTS: A C. difficile infection anytime within 2 years prior to total hip arthroplasty was independently associated with higher odds of PJI (OR [odds ratio]: 1.49 [95% CI (confidence interval) 1.09 to 2.02, P = .014]). Proximity of C. difficile infection to arthroplasty was associated with increased risk of PJI (infection 0 to 3 months before THA: OR 2.01 [95% CI 1.23 to 3.20], infection 3 to 6 months before THA: OR 1.84 [95% CI 1.06 to 3.04], infection 6 to 12 months before THA: OR 1.10 [95% CI 0.65 to 1.77], infection 1 to 2 years before THA: OR 1.40 [95% CI 0.94 to 2.06]). CONCLUSIONS: A C. difficile infection prior to THA is an independent risk factor for PJI. Proximity of C. difficile infection is associated with increased risk of PJI. Future investigations should evaluate how to adequately optimize patients prior to THA and pursue strategies to determine appropriate timing for proceeding with THA.

In Vivo Findings of a Novel Focal Ablation Catheter: Focused Electric Field Catheter Tip.

Current catheter designs used for radiofrequency (RF) in cardiac tissue achieve limited ablation depth as lesion size is driven heavily by resistive heating at the tissue surface. A catheter with a truncated, dome-shaped tip with a toroidal surface designed for focal RF ablation was recently described. This in vivo study compares lesion characteristics between a second-generation focused electric field (FEF) catheter vs a standard irrigated catheter using RF energy in a beating heart model. We performed in vivo ablations using RF energy with the FEF ablation catheter tip (Focused Therapeutics) and an irrigated Blazer catheter (Boston Scientific) under identical power, duration, and irrigation rates. In addition, RF dosing at high power and duration was examined using the FEF catheter. Intracardiac echocardiography was used to evaluate steam pops and catheter tip angle relative to the tissue surface. Studies were terminal and lesion size was measured following 2,3,5-triphenyltetrazolium chloride staining. Ablations were performed in 6 swine (FEF, n = 31; control, n = 8). FEF ablation lesions (n = 7) were deeper (15.6 ± 2.6 mm vs 7.5 ± 1.9 mm; P < 0.001) and wider (18.4 ± 2.9 mm vs 12.6 ± 2.4 mm; P < 0.001) than lesions delivered with the control irrigated catheter (n = 8) under the same parameters. Thirty-two percent (n = 10 of 31) of lesions delivered from the left ventricle endocardial surface using the FEF catheter were transmural. No steam pops were observed with delivery of FEF lesions (n = 31). The angle of incidence did not significantly affect FEF lesion size. In this in vivo preclinical study, the FEF catheter, which provides focused energy delivery, resulted in significantly larger lesions than the irrigated control catheter without steam pops. Approximately one-third of ablations with the FEF catheter delivered from the endocardial left ventricular surface resulted in transmural lesions.

Cardioneuroablation for the management of patients with recurrent vasovagal syncope and symptomatic bradyarrhythmias: the CNA-FWRD Registry.

BACKGROUND: Cardioneuroablation has been emerging as a potential treatment alternative in appropriately selected patients with cardioinhibitory vasovagal syncope (VVS) and functional AV block (AVB). However the majority of available evidence has been derived from retrospective cohort studies performed by experienced operators. METHODS: The Cardioneuroablation for the Management of Patients with Recurrent Vasovagal Syncope and Symptomatic Bradyarrhythmias (CNA-FWRD) Registry is a multicenter prospective registry with cross-over design evaluating acute and long-term outcomes of VVS and AVB patients treated by conservative therapy and CNA. RESULTS: The study is a prospective observational registry with cross-over design for analysis of outcomes between a control group (i.e., behavioral and medical therapy only) and intervention group (Cardioneuroablation). Primary and secondary outcomes will only be assessed after enrollment in the registry. The follow-up period will be 3 years after enrollment. CONCLUSIONS: There remains a lack of prospective multicentered data for long-term outcomes comparing conservative therapy to radiofrequency CNA procedures particularly for key outcomes including recurrence of syncope, AV block, durable impact of disruption of the autonomic nervous system, and long-term complications after CNA. The CNA-FWRD registry has the potential to help fill this information gap.

Rheumatoid Arthritis Is Not a Contraindication to Unicompartmental Knee Arthroplasty.

BACKGROUND: Rheumatoid arthritis (RA) has historically been considered a contraindication for unicompartmental knee arthroplasty (UKA). However, the widespread use of disease-modifying antirheumatic drugs has substantially improved the management of RA and prevented disease progression. The objective of this study was to ascertain whether RA impacts UKA revision-free survivorship. METHODS: Patients undergoing UKA from 2010 to 2021 were identified in an administrative claims database (n = 105,937) using Current Procedural Terminology code 27446. All patients who underwent UKA who had a diagnosis of RA with a minimum of 2-year follow-up (n = 1,422) were propensity score matched based on age, sex, and Elixhauser Comorbidity Index to those who did not have RA (n = 1,422). Laterality was identified using the 10th Revision of International Classification of Diseases codes. The primary outcome was ipsilateral revision to total knee arthroplasty (TKA) within 2 years, and the secondary outcome was ipsilateral revision at any time. RESULTS: Among the 1,422 patients who had a UKA and a diagnosis of RA, 37 patients (2.6%) underwent conversion to TKA within 2 years, and 48 patients (3.4%) underwent conversion to TKA at any point. In comparison, 28 patients (2.0%) in the propensity-matched control group underwent conversion to TKA within 2 years, and 40 patients (2.8%) underwent conversion to TKA at any point. Statistical analysis revealed no significant difference in conversion to TKA between patients who had and did not have RA, either within 2 years (P = .31) or anytime (P = .45). CONCLUSIONS: Patients who had RA and underwent UKA did not have an increased risk of revision to TKA compared to those who did not have RA. This may indicate that modern management of RA could allow for expanded UKA indications for RA patients.

Individualizing a Total Knee Arthroplasty with Three-Dimensional Planning.

Total knee arthroplasty (TKA) is evolving from mechanical alignment to more individualized alignment options in an attempt to improve patient satisfaction. Thirteen-year survival of kinematically aligned prostheses has recently been shown to be similar to mechanically aligned TKA, allaying concerns of long-term failure of this newer individualized technique. There is a complex inter-relationship of three-dimensional knee and limb alignment for a TKA. This article will review planning parameters necessary to individualize each knee, along with a discussion of how these parameters are related in three dimensions. Future use of computer software and machine learning has the potential to identify the ideal surgical plan for each patient. In the meantime, the material presented here can assist surgeons as newer individual alignment planning becomes a reality.

Erratum to: Association between Modifiable Risk Factors and Levels of Blood-Based Biomarkers of Alzheimer's and Related Dementias in the Look AHEAD Cohort.

[This corrects the article DOI: 10.14283/jarlife.2024.1.].

Correlation of serum level of squamous cell carcinoma antigen with severity of cutaneous psoriasis, assessed using the simplified psoriasis index.

BACKGROUND: Squamous cell carcinoma antigen (SCCA) is a biomarker of disease progression in squamous cell carcinoma but also contributes to the pathogenesis of psoriasis. Eight previous studies have shown a correlation between psoriasis severity, assessed using the Psoriasis Assessment Severity Index or body surface area, and serum level of SCCA, mainly SCCA2, assessed by means of non-commercial tests. We examined the correlation between serum SCCA level, measured with a commercial kit, and psoriasis severity assessed using the Simplified Psoriasis Index (SPI). METHODS: We conducted a prospective, non-interventional, single-centre study at the University Hospital of Tours over 18 months. The primary endpoint was same-day measurement of serum SCCA level and the psoriasis severity score on the professional version of the SPI (proSPI-s) at both baseline and follow-up. Secondary endpoints were same-day measurement of serum SCCA level and the proSPI psychosocial score (proSPI-p), proSPI treatment score, Dermatology Life Quality Index (DLQI), and inflammation parameters (C-reactive protein level, neutrophil-to-lymphocyte ratio). RESULTS: We included 50 psoriasis patients. Serum SCCA level was correlated with the proSPI-s at baseline and follow-up (Spearman r = 0.686 and r = 0.674, p < 0.0001) for both. It was correlated with the proSPI-p and DLQI. Serum SCCA level was not correlated with either neutrophil-to-lymphocyte ratio (r = 0.083) or C-reactive protein level (r = 0.192). CONCLUSION: This study is the first to correlate serum SCCA level with proSPI-s. Moreover, SCCA was measured using a widely available kit. SCCA may be used to assess the severity of psoriasis.

Posteromedial Periarticular Injection in Total Knee Arthroplasty: A Cadaveric Study.

Achieving optimal pain control in total knee arthroplasty has improved with the use of regional anesthesia and periarticular injections (PAIs). When performing a PAI, the relative location of the anesthetic spread is not well defined in comparison with an adductor canal block (ACB). In this study, our aim was to evaluate the location of posteromedial PAI spread compared with a surgeon administered ACB. One PAI and one surgeon-administered ACB were performed in the contralateral limbs of four human cadavers. The injectate was composed of methylene blue dye to visually inspect the dye spread from the tip of the needle. Dissections were performed on each cadaver to quantify the dye spread from the tip of the needle and compare the location of the dye spread. Dye spread location was characterized as either entering the adductor canal or including the posterior capsule. The mean distance of dye spread from the needle tip to the proximal most aspect of the dyed tissue was 10.125 cm in the ACB group compared with 6.5 cm in the posteromedial PAI group. In the ACB group, 4 of 4 injections were present in the adductor canal block group compared with 3 of 4 in the posteromedial PAI group. The posteromedial PAI group also had 3 of 4 injections involve the area around the posterior capsule compared with 0 of 4 in the ACB group. Posteromedial PAI appears to provide local delivery to both the adductor canal and the posterior capsule. Intraoperative, surgeon-administered ACB reliably delivers injectate to the adductor canal only but may allow for more proximal dye spread. Posteromedial PAI may provide a benefit in delivering injectate to the posterior capsule in addition to the ACB. Additional clinical studies are necessary to determine the clinical effects of this finding.

Delays in accessing high-quality care for newborns in East Africa: An analysis of survey data in Malawi, Mozambique, and Tanzania.

Background: Despite the existence of evidence-based interventions, substantial progress in reducing neonatal mortality is lagging, indicating that small and sick newborns (SSNs) are likely not receiving the care they require to survive and thrive. The 'three delays model' provides a framework for understanding the challenges in accessing care for SSNs. However, the extent to which each delay impacts access to care for SSNs is not well understood. To fill this evidence gap, we explored the impact of each of the three delays on access to care for SSNs in Malawi, Mozambique, and Tanzania. Methods: Secondary analyses of data from three different surveys served as the foundation of this study. To understand the impact of delays in the decision to seek care (delay 1) and the ability to reach an appropriate point of care (delay 2), we investigated time trends in place of birth disaggregated by facility type. We also explored care-seeking behaviours for newborns who died. To understand the impact of delays in accessing high-quality care after reaching a facility (delay 3), we measured facility readiness to manage care for SSNs. We used this measure to adjust institutional delivery coverage for SSN care readiness. Results: Coverage of institutional deliveries was substantially lower after adjusting for facility readiness to manage SSN care, with decreases of 30 percentage points (pp) in Malawi, 14 pp in Mozambique, and 24 pp in Tanzania. While trends suggest more SSNs are born in facilities, substantial gaps remain in facilities' capacities to provide lifesaving interventions. In addition, exploration of care-seeking pathways revealed that a substantial proportion of newborn deaths occurred outside of health facilities, indicating barriers in the decision to seek care or the ability to reach an appropriate source of care may also prevent SSNs from receiving these interventions. Conclusions: Investments are needed to overcome delays in accessing high-quality care for the most vulnerable newborns, those who are born small or sick. As more mothers and newborns access health services in low- and middle-income countries, ensuring that life-saving interventions for SSNs are available at the locations where newborns are born and seek care after birth is critical.

The impact of anticholinergic burden on clinical outcomes in older hospitalised surgical patients.

Polypharmacotherapy is an ever-increasing issue with an ageing patient population. Anticholinergic medications make up a large proportion of patient medication but cause significant side effects, contributing to well-documented issues within the older population and in hospital medicine. This review explores the documented impact of anticholinergic burden in older surgical patients on postoperative delirium, infection, length of stay and readmission, urinary retention, ileus and mortality. It also highlights the need for further high-quality research into anticholinergic burden management among older surgical patients to further impact practice and policy in the area.

Quantifying forms and functions of intestinal bile acid pools in mice.

Bile acids (BAs) are gastrointestinal metabolites that serve dual functions in lipid absorption and cell signaling. BAs circulate actively between the liver and distal small intestine (i.e., ileum), yet the dynamics through which complex BA pools are absorbed in the ileum and interact with intestinal cells in vivo remain ill-defined. Through multi-site sampling of nearly 100 BA species in individual wild type mice, as well as mice lacking the ileal BA transporter, Asbt/Slc10a2, we calculate the ileal BA pool in fasting C57BL/6J mice to be ~0.3 µmoles/g. Asbt-mediated transport accounts for ~80% of this pool and amplifies size, whereas passive absorption explains the remaining ~20%, and generates diversity. Accordingly, ileal BA pools in mice lacking Asbt are ~5-fold smaller than in wild type controls, enriched in secondary BA species normally found in the colon, and elicit unique transcriptional responses in cultured ileal explants. This work quantitatively defines ileal BA pools in mice and reveals how BA dysmetabolism can impinge on intestinal physiology.

Association between Modifiable Risk Factors and Levels of Blood-Based Biomarkers of Alzheimer's and Related Dementias in the Look AHEAD Cohort.

Background: Emerging evidence suggests that a number of factors can influence blood-based biomarker levels for Alzheimer's disease (AD) and Alzheimer's related dementias (ADRD). We examined the associations that demographic and clinical characteristics have with AD/ADRD blood-based biomarker levels in an observational continuation of a clinical trial cohort of older individuals with type 2 diabetes and overweight or obesity. Methods: Participants aged 45-76 years were randomized to a 10-year Intensive Lifestyle Intervention (ILI) or a diabetes support and education (DSE) condition. Stored baseline and end of intervention (8-13 years later) plasma samples were analyzed with the Quanterix Simoa HD-X Analyzer. Changes in Aß42, Aß40, Aß42/Aß40, ptau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were evaluated in relation to randomization status, demographic, and clinical characteristics. Results: In a sample of 779 participants from the Look AHEAD cohort, we found significant associations between blood-based biomarkers for AD/ADRD and 15 of 18 demographic (age, gender, race and ethnicity, education) and clinical characteristics (APOE, depression, alcohol use, smoking, body mass index, HbA1c, diabetes duration, diabetes treatment, estimated glomerular filtration rate, hypertension, and history of cardiovascular disease) . Conclusions: Blood-based biomarkers of AD/ADRD are influenced by common demographic and clinical characteristics. These factors should be considered carefully when interpreting these AD/ADRD blood biomarker values for clinical or research purposes.

Surpoint algorithm for improved guidance of ablation for ventricular tachycardia (SURFIRE-VT): A pilot study.

INTRODUCTION: The utility of ablation index (AI) to guide ventricular tachycardia (VT) ablation in patients with structural heart disease is unknown. The aim of this study was to assess procedural characteristics and clinical outcomes achieved using AI-guided strategy (target value 550) or conventional non-AI-guided parameters in patients undergoing scar-related VT ablation. METHODS: Consecutive patients (n = 103) undergoing initial VT ablation at a single center from 2017 to 2022 were evaluated. Patient groups were 1:1 propensity-matched for baseline characteristics. Single lesion characteristics for all 4707 lesions in the matched cohort (n = 74) were analyzed. The impact of ablation characteristics was assessed by linear regression and clinical outcomes were evaluated by Cox proportional hazard model. RESULTS: After propensity-matching, baseline characteristics were well-balanced between AI (n = 37) and non-AI (n = 37) groups. Lesion sets were similar (scar homogenization [41% vs. 27%; p = .34], scar dechanneling [19% vs. 8%; p = .18], core isolation [5% vs. 11%; p = .4], linear and elimination late potentials/local abnormal ventricular activities [35% vs. 44%; p = .48], epicardial mapping/ablation [11% vs. 14%; p = .73]). AI-guided strategy had 21% lower procedure duration (-47.27 min, 95% confidence interval [CI] [-81.613, -12.928]; p = .008), 49% lower radiofrequency time per lesion (-13.707 s, 95% CI [-17.86, -9.555]; p < .001), 21% lower volume of fluid administered (1664 cc [1127, 2209] vs. 2126 cc [1750, 2593]; p = .005). Total radiofrequency duration (-339 s [-24%], 95%CI [-776, 62]; p = .09) and steam pops (-155.6%, 95% CI [19.8%, -330.9%]; p = .08) were nonsignificantly lower in the AI group. Acute procedural success (95% vs. 89%; p = .7) and VT recurrence (0.97, 95% CI [0.42-2.2]; p = .93) were similar for both groups. Lesion analysis (n = 4707) demonstrated a plateau in the magnitude of impedance drops once reaching an AI of 550-600. CONCLUSION: In this pilot study, an AI-guided ablation strategy for scar-related VT resulted in shorter procedure time and average radiofrequency time per lesion with similar acute procedural and intermediate-term clinical outcomes to a non-AI-guided approach utilizing traditional ablation parameters.

A Structure-function Analysis of Hepatocyte Arginase 2 Reveals Mitochondrial Ureahydrolysis as a Determinant of Glucose Oxidation.

BACKGROUND & AIMS: Restoring hepatic and peripheral insulin sensitivity is critical to prevent or reverse metabolic syndrome and type 2 diabetes. Glucose homeostasis comprises in part the complex regulation of hepatic glucose production and insulin-mediated glucose uptake and oxidation in peripheral tissues. We previously identified hepatocyte arginase 2 (Arg2) as an inducible ureahydrolase that improves glucose homeostasis and enhances glucose oxidation in multiple obese, insulin-resistant models. We therefore examined structure-function determinants through which hepatocyte Arg2 governs systemic insulin action and glucose oxidation. METHODS: To do this, we generated mice expressing wild-type murine Arg2, enzymatically inactive Arg2 (Arg2H160F) and Arg2 lacking its putative mitochondrial targeting sequence (Arg2Δ1-22). We expressed these hepatocyte-specific constructs in obese, diabetic (db/db) mice and performed genetic complementation analyses in hepatocyte-specific Arg2-deficent (Arg2LKO) mice. RESULTS: We show that Arg2 attenuates hepatic steatosis, independent of mitochondrial localization or ureahydrolase activity, and that enzymatic arginase activity is dispensable for Arg2 to augment total body energy expenditure. In contrast, mitochondrial localization and ureahydrolase activity were required for Arg2-mediated reductions in fasting glucose and insulin resistance indices. Mechanistically, Arg2Δ1-22 and Arg2H160F failed to suppress glucose appearance during hyperinsulinemic-euglycemic clamping. Quantification of heavy-isotope-labeled glucose oxidation further revealed that mistargeting or ablating Arg2 enzymatic function abrogates Arg2-induced peripheral glucose oxidation. CONCLUSION: We conclude that the metabolic effects of Arg2 extend beyond its enzymatic activity, yet hepatocyte mitochondrial ureahydrolysis drives hepatic and peripheral oxidative metabolism. The data define a structure-based mechanism mediating hepatocyte Arg2 function and nominate hepatocyte mitochondrial ureahydrolysis as a key determinant of glucose oxidative capacity in mammals.